Technetium-99m (99mTc) is the most widely available radioisotope used for diagnostic radiophamarceuticals, with advantages of preferable properties for clinical use such as short half-life (6 h), gamma energy (140 keV) appropriate for obtaining gamma picture, low cost and general usefulness. 99mTc generally forms a complex with compounds having unpaired electrons such as isocyanate, amine, carboxyl, and thiol, and thus the complex formed is used as an imaging agent or a labelling agent of various tissues, which include lung, liver, and brain.
However, the method for the preparation of the technetium-radiolabelled thiol compound (hereinafter called a sulfide compound) is very limited because the compound containing thiol is very unstable. Accordingly, the compound is easily oxidized during the labelling reaction with 99mTc, and forms a sulfide form and thus easily changes into a disulfide form [Cappozi, G. et al. The Chemistry of the Thiol Group, pt. 2; Wiley: N.Y., 1974, p. 785].
Up to now, the method for radiolabelling sulfide compound was carried out simultaneously with the chelation of technetium and the deprotection of the S-protected precursor synthesized in advance. For example, the method of labelling technetium for radiophamarceuticals is described in more detail in the following. First, a S-protected precursor is synthesized by being stirred with triphenylmethanol at room temperature under acidic catalysis for more than 1 hour; then the S-protected precursor is refluxed under acidic catalysis for more than 30 minutes before labelling 99mTc; and finally 99mTc is labelled [Oya, s. et al. Nuclear Medicine and Biology 1998, 25, 135–140; Dezutter, A. Journal of Labelled Compounds and phamarceuticals 1999, 42, 309–324]. Using the above method, diamine dithiol as a ligand was synthesized, and the usefulness of the chelation for radiopharmaceuticals was recognized.
However, the above-mentioned method has disadvantages such as the S-protected precursor is synthesized through several steps and the deprotection of the S-protected precursor and the reduction of pertechnetate should be carried out simultaneously.
Among isotopes of rhenium, rhenium-186 (186Re) and rhenium-188 (188Re) are homologous elements with technetium, and they have the properties of emitting both beta ray that is appropriate for medical use and gamma ray that is possible picturing. Practically, 186Re and 188Re are being used as radiophamarceuticals that can be applied to the remedy of bone pain generated by secondary bone metastasis of prostate cancer, lung cancer, breast cancer, etc. Since 186Re and 188Re have similar chemical properties with technetium, the labelling method of technetium can be applied to the method of labelling rhenium through some improvements[Lin, W. et al. J. Nucl. Med. 1997, 24, 590–595; Lewington, V. J. et al. Eur. J. Nucl. Med. 1993, 20, 60–74; Lewington, V. J. et al. Phys. Med. Biol. 1996, 41, 2027–2042; Hashimoto, K. et al. Appl. Radiat. Isot. 1996, 47, 195–199].
Therefore, there have been continuous needs to develop a method which simultaneously carries out the reduction of disulfide compounds and reduction of pertechnetate or perrhenate under the mild condition, namely, a method to directly produce the technetium or rhenium complex with sulfide compounds from disulfide compounds is carried out.
Accordingly, the present inventors have completed the present invention in the course to develop a new labelling method that satisfies all the above-mentioned conditions by certifying that borohydride exchange resin can simultaneously carry out reduction of disulfide compounds and reduction of pertechnetate or perrhenate under the mild condition and that the labelling of technetium or rhenium with sulfide compounds with high radiochemical purity and high yield can be carried out.